ESCRT-I and PTPN23 mediate microautophagy of ubiquitylated tau aggregates.

Protein aggregates are degraded by both the autophagy-lysosomal and the ubiquitin-proteasome pathways. Macroautophagy and microautophagy, two forms of the autophagy-lysosomal pathway, are widely conserved across eukaryotes. While macroautophagy has been extensively studied in the context of degradation of protein aggregates, microautophagy remains less explored. Here, we identify the UBAP1-containing ESCRT-I complex and PTPN23 as new regulators for degradation of aggregated proteins through an unbiased genome-wide CRISPR knockout screen, using a cell line expressing tau repeat domain (tauRD) aggregates. ESCRT-I recognizes ubiquitylated tauRD via the UEV domain of TSG101. The accessory protein PTPN23, instead of ESCRT-II, bridges ESCRT-I and ESCRT-III to complete the endosomal microautophagy of ubiquitylated tauRD aggregates. Our results uncover the molecular mechanism underlying the degradation of tau aggregates by endosomal microautophagy.